Unusual Formation of 1,2,4-Oxadiazine Core in Reaction of Amidoximes with Maleic or Fumaric Esters

Abstract

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents’ electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, 1H, and 13C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction.

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

“…Recently, Boyarskiy with coworkers reported that the reaction between amidoximes and maleic esters in NaOH/DMSO medium provided 1,2,4-oxadiazin-5(6 H )-ones instead of the expected 1,2,4-oxadiazoles ( Scheme 17 ). The base replacement to t -BuONa and increasing the amidoxime amount up to 2.5 eq allowed them to obtain hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4 H -1,2,4-oxadiazin-5(6 H )-ones [ 112 ].…”